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Association of Antiepileptic Drug Usage, Trace Elements and Thyroid Hormone Status

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Association of Antiepileptic Drug Usage, Trace Elements and Thyroid Hormone Status C Zevenbergen, Trace elements and thyroid 174:4 425–432 Clinical Study T I M Korevaar, hormones A Schuette and others Association of antiepileptic drug usage, trace elements and thyroid hormone status Chantal Zevenbergen1,2,*, Tim I M Korevaar1,2,*, Andrea Schuette3,*, Robin P Peeters1,2, Marco Medici1,2, Theo J Visser1,2, Lutz Schomburg3 and W Edward Visser1,2 1Department of Internal Medicine and 2Rotterdam Thyroid Center, Erasmus Medical Center, Wytemaweg 80, 3015 Correspondence CN Rotterdam, The Netherlands and 3Institut fu¨ r Experimentelle Endokrinologie, Charite´ -Universita¨ tsmedizin should be addressed Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany to W E Visser *(C Zevenbergen, T I M Korevaar, A Schuette contributed equally to this work) Email [email protected] Abstract Background: Levels of thyroid hormone (TH) and trace elements (copper (Cu) and selenium (Se)) are important for development and function of the brain. Anti-epileptic drugs (AEDs) can influence serum TH and trace element levels. As the relationship between AEDs, THs, and trace elements has not yet been studied directly, we explored these interactions. Method: In total 898 participants, from the Thyroid Origin of Psychomotor Retardation study designed to investigate thyroid parameters in subjects with intellectual disability (ID), had data available on serum Se, Cu, thyroid stimulating hormone (TSH), free thyroxine (FT4), tri-iodothyronine (T3), reverse T3,T4, and thyroxine-binding globulin (TBG); 401 subjects were on AED treatment. Differences in trace elements according to medication usage was investigated using ANOVA, and associations between trace elements and thyroid parameters were analysed using (non-) linear regression models. Results: Study participants were not deficient in any of the trace elements analyzed. AED (carbamazepine, valproate and phenytoin) usage was negatively associated with serum Se and showed compound-specific associations with Cu levels. After correction for drug usage, Se was positively associated with TSH levels, negatively associated with FT4 levels, and positively with T3 levels. Cu was positively associated with T4,T3, and rT3, which was largely dependent on TBG levels. European Journal of Endocrinology Conclusion: The subjects with ID did not display profound deficiencies in trace element levels. AEDs were associated with serum Se and Cu levels, while serum Se and Cu were also associated with thyroid parameters. Further studies on the underlying mechanisms and potential clinical importance are warranted. European Journal of Endocrinology (2016) 174, 425–432 Introduction Thyroid hormone (TH) is important for the normal among endocrine disorders (4) at varying prevalences development and energy metabolism of almost all according to the group of patients that is being tissues (1). The thyroid gland pre-dominantly secretes studied (5, 6). the inactive pro-hormone thyroxine (T4), which is locally Essential trace elements, like Se and copper (Cu), are converted to the active form tri-iodothyronine (T3)by micronutrients that are present in low concentrations in selenium (Se)-dependent enzymes of the family of the human body and are dependent on a sufficiently high iodothyronine deiodinases (2).T3 mediates its dietary intake. Trace elements are essential for many major effects by binding to nuclear TH receptors (TRs) enzymatic reactions and are therefore important for which regulate the transcription of target genes (3). proper functioning of biochemical pathways and the Abnormalities in TH status are commonly found endocrine system (7). www.eje-online.org Ñ 2016 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-15-1081 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 03:35:18AM via free access Clinical Study C Zevenbergen, Trace elements and thyroid 174:4 426 T I M Korevaar, hormones A Schuette and others Sufficient levels of both TH and trace elements are The aim of this study was to analyze the associations important for normal development of the brain (8). between AEDs, Se, Cu, and thyroid parameters using Abnormalities in TH signaling can give rise to neurocog- the TOP-R cohort. nitive impairment, as illustrated by subjects with mutations in the gene encoding the TH transporter monocarboxylate transporter 8 (MCT8) (9, 10) or in the Subjects and methods a TR THRA (encoding TR ) (11, 12, 13, 14). Adequate levels TOP-R study of Cu are also important for normal development of the brain, as Cu is important in energy metabolism, anti- The TOP-R study is a nation-wide cohort study in The oxidative defense, and the production of neurotransmit- Netherlands, which was designed to investigate thyroid ters (15). Also, it was shown that TH or Cu deficiencies parameters in subjects with intellectual disability (ID). resulted in similar defects during rodent cerebral cortical The study population has been described in detail before development (16). The brain appears to preserve Se levels (23). In short, subjects were excluded if the aetiology of the during Se shortage, as rats on a Se deficient diet did not ID was known. Information about other medication was G display any neurological symptoms, because of only unavailable. Mean age was 47.9 0.5 years, and 47% were slightly reduced brain Se levels (17).However,mice women. The study was approved by the medical ethics lacking selenoprotein P (SelP), which is an important Se committee of the Erasmus University Medical Centre. carrier, showed very low brain Se levels together with Written informed consent was obtained from the legally authorized representatives. Of the 946 eligible movement disorders and occasional seizures (18). individuals, data on TH and trace element serum levels Only limited data on the relationship between TH and were available in 898 subjects, and information about Se and Cu are currently available. It was shown in rats that thyroid medication (anti-thyroid drugs and L-T replace- adequate Se in nutrition supports TH synthesis and 4 ment therapy) was available in 806 subjects and about metabolism and protects the thyroid gland from AEDs in 786 subjects. Full case analyses according to this damage by excessive exposure to reactive chemicals (19). data did not change the results (data not shown). After Furthermore, in humans, high levels of Cu were associated exclusion of subjects that used thyroid-interfering medi- with higher levels of both T and T (20). As a corollary, 3 4 cation (nZ40) and/or thyroid peroxidase antibodies Bastian et al. (16, 21, 22) showed in different rat (TPOAb) positive individuals (cut-off O60 IU/ml; nZ24), studies that fetal deficiency of Cu resulted in impaired 834 subjects were included in one or more analyses. After European Journal of Endocrinology TH-regulated brain gene expression. While these studies exclusion, 372 of 725 eligible patients used AEDs (51.3%). suggested an interaction of the trace elements Se and Cu and TH during brain development, its relevance for humans is unknown. Measurements of thyroid status, Se, and Cu In the Thyroid Origin of Psychomotor Retardation Serum samples were stored frozen at K20 8C. Serum T4, (TOP-R) study, thyroid parameters of subjects with FT4, and thyroid-stimulating hormone (TSH) were intellectual disability (ID) were extensively profiled (23). measured by chemiluminescence assays (Vitros ECI In this cohort, it has been shown that TH profiles in Immunodiagnostic System; Ortho-Clinical Diagnostics, subjects without anti-epileptic drugs (AEDs) were com- Inc., Rochester, NY, USA). T3 was measured using an parable with the general population. However, AEDs were in-house RIA and rT3 using a commercial RIA (Immuno- strongly associated with decreased T4, free T4 (FT4), T3, diagnostic Systems, Scottsdale, AZ, USA). Thyroxine- and rT3 levels which is in agreement with other studies binding globulin (TBG) and TPO antibodies were (24, 25, 26). It has been speculated that the changed determined by immunoassay (Immulite 2000, Siemens, thyroid parameters in patients that use AEDs can be Breda, The Netherlands). Se and Cu concentrations were explained by an influence of AEDs on binding proteins determined by total reflection X-ray fluorescence spectro- (27), a stimulation of hepatic degradation or conjugation scopy (34). The method was validated with a Seronorm of TH (28) or an altered peripheral deiodinase activity (23). standard (Sero AS, Billingstad,Norway).Briefly,all Interestingly, AEDs have been associated with changes in samples were diluted 1:1 in a gallium-containing solvent serum levels of Se and Cu (23, 29, 30, 31, 32, 33). However, for standardization. The analysis was performed in the complex relationship between AEDs, THs, Se, and Cu duplicate, and the results of each sample differed by has never been directly studied. !20% for both Se and Cu. In every measurement run, www.eje-online.org Downloaded from Bioscientifica.com at 09/25/2021 03:35:18AM via free access Clinical Study C Zevenbergen, Trace elements and thyroid 174:4 427 T I M Korevaar, hormones A Schuette and others a human control serum was included, allowing the A P<0.0001 B P=0.0009 calculation of an intra-assay coefficient of variation of 120 120 g/l) g/l) µ 7% (Se) and 8% (Cu) and an inter-assay coefficient of µ variation of 12% (Se) and 18% (Cu) respectively. 110 110 100 100 Selenium in ( Selenium in ( Statistical analysis No Yes No Yes To satisfy model assumptions, TSH levels were logarithmi- Carbamazepine usage Valproate usage cally transformed. The association between trace elements CDP<0.0001 P=0.04 and thyroid parameters was investigated using ordinary 2800 2800 g/l) least squares linear regression models with restricted cubic g/l) µ µ 2600 2600 splines utilizing three to five knots. Figures show back- transformed axis values for TSH, and all associations were 2400 2400 Copper in ( adjusted for sex, age, and relevant medication usage Copper in ( (covariates set to mean levels or most appearing category). 2200 2200 The analyses were adjusted for medication usage when a No Yes No Yes Carbamazepine usage Valproate usage drug was associated with a thyroid function parameter in a backward linear regression analysis, utilizing a cut-off of E P=0.0009 2800 P!0.15.
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